Isocyanato rhodium (I) zwitterionic complex, preparation method thereof, micelle, nanodiagnostic probe and anticancer drug

Abstract

The present invention provides an isocyanato rhodium (I) zwitterionic complex, a preparation method thereof, micelles, a nano-diagnosis and treatment probe, and an anticancer drug. The isocyanato rhodium (I) zwitterionic complex has a rhodium (I) atom as the metal center, an aromatic isonitrile and a 4-isocyanate as ligands, is hydrophobic and hydrophilic, and has near-infrared second-zone luminescence properties. It is mixed with PEGylated liposomes, and the PEGylated liposomes encapsulate the isocyanato rhodium (I) zwitterionic complex through hydrophobic-hydrophobic interactions to obtain isocyanato rhodium (I) zwitterionic complex micelles. The micelles have biocompatibility and stability, near-infrared second-zone luminescence imaging, and anticancer activity. The micelles can be used for nano-diagnosis and treatment probes and anticancer drugs, and have potential application prospects in the field of biomedicine.

Description

Technical Field

[0001] The present invention belongs to the technical field of supramolecular medicine, and specifically relates to an isocyanate rhodium (I) zwitterion complex, a preparation method thereof, micelles, nano-diagnostic and therapeutic probes, and anticancer drugs. Background Art

[0002] Compared with traditional imaging technology, nano-diagnostic and therapeutic systems that combine diagnostic and therapeutic functions have significant advantages and great potential in early tumor detection, pharmacokinetics, personalized treatment, efficacy monitoring and evaluation.

[0003] Compared with conventional optical imaging in the visible (400 nm–650 nm) and first near-infrared window (NIR-I, 650 nm–900 nm), imaging in the second near-infrared region (NIR-II, 1000–1700 nm) offers higher signal-to-noise ratios, better image quality, and deeper tissue penetration. In recent years, organic molecules, carbon nanotubes, quantum dots, and upconversion nanoparticles have been used for NIR-II in vivo imaging, particularly in real-time vasculature visualization and tumor resection. However, organic small molecule dyes and inorganic nanomaterials are often hampered by issues such as susceptibility to photobleaching, small Stokes shifts, and unknown toxicity and slow elimination pharmacokinetics, which, to a certain extent, limit the application and development of these materials.

[0004] On the other hand, organometallic complexes have emerged as promising new metal drug candidates and are receiving increasing attention as cancer chemotherapy agents. Compared to organic small molecule anticancer drugs, metal-based anticancer drugs inhibit cancer cell division and induce apoptosis by inducing DNA damage and disrupting DNA repair processes (such as ligand exchange). In the 1960s, the discovery of cisplatin made it an effective anticancer drug and promoted the development of metal chemotherapy drugs. In clinical practice, approximately 50-70% of cancer patients are treated with platinum drugs such as cisplatin, carboplatin, and oxaliplatin. However, the emergence of chemotherapy resistance and the severe side effects associated with platinum drugs have prompted the study of other transition metal complexes with anticancer activity. Summary of the Invention

[0005] The present invention provides a novel isocyanate rhodium (I) zwitterionic complex, which has both hydrophobicity and hydrophilicity, can emit light in the near-infrared region II for imaging, and has application prospects in the field of anticancer activity research.

[0006] The technical solution of the present invention is: an isocyanate rhodium (I) zwitterionic complex, the chemical structural formula of which is:

[0007]

[0008] Wherein, Ar is a benzene-type aromatic hydrocarbon or a derivative thereof, and R is an acid radical ion.

[0009] In the present invention, R includes but is not limited to

[0010]

[0011] In the present invention, Ar includes but is not limited to

[0012]

[0013] The present invention also provides a method for synthesizing the isocyanate rhodium (I) zwitterionic complex, the synthesis route of which is as follows: Figure 1 As shown, that is, the synthesis method includes the following steps:

[0014] (1) Synthesis of isocyanato rhodium-chloride intermediate:

[0015] Under nitrogen protection, an aromatic isonitrile ligand, 1,5-cyclooctadiene rhodium chloride dimer and a solvent are added to a container and stirred to mix uniformly to obtain an isonitrile rhodium-chloride intermediate;

[0016] (2) Synthesis of isocyanate rhodium (I) zwitterionic complexes:

[0017] Under nitrogen protection, the isonitrile rhodium-chloride intermediate prepared in step (1), 4-isocyanatobenzene salt and solvent are added into a container, stirred and mixed uniformly, and the isonitrile rhodium (I) zwitterionic complex is obtained by reaction.

[0018] In the step (1), the aromatic isonitrile ligand includes but is not limited to one or more of 1-isocyanobenzene, 2,6-dimethyl-1-isocyanobenzene, 2-isocyanonaphthalene, 1-isocyanonaphthalene, 2-methyl-1-isocyanonaphthalene, and 4-isocyanobiphenyl.

[0019] In the step (1), the solvent includes but is not limited to one or more of dichloromethane, methanol, tetrahydrofuran, and dimethyl sulfoxide.

[0020] In the step (1), preferably, the stirring is performed for 15 to 60 minutes.

[0021] In the step (1), the container is not limited. Preferably, the container is equipped with a stirrer and an air guide tube, such as a three-necked round-bottom flask.

[0022] In the step (1), the molar ratio of the aromatic isonitrile ligand to the 1,5-cyclooctadiene rhodium chloride dimer is substantially 6:1.

[0023] In the step (2), the Rh-Cl of the isocyanide rhodium-chloride intermediate is neutral and has no charge. After coordination with 4-isocyanate benzene salt, the metal rhodium is a cation and the acid radical ion is an anion.

[0024] Preferably, the product after the reaction in step (2) is transferred to a dialysis bag, dialyzed in water, and then freeze-dried to obtain a pure solid product. Preferably, the dialysis is performed for 12 hours to 60 hours.

[0025] In the step (2), the 4-isocyanobenzene salt includes but is not limited to 4-isocyanobenzene sodium salt, such as one or more of sodium 4-isocyanobenzene benzoate, sodium 4-isocyanobenzene sulfonate, sodium 4-isocyanobenzene acyloxyethyl sulfonate, and sodium 4-isocyanobenzene acyloxyethyl sulfonate.

[0026] In the step (2), the solvent includes but is not limited to one or more of dichloromethane, methanol, tetrahydrofuran, and dimethyl sulfoxide.

[0027] In the step (2), the molar ratio of the isonitrile rhodium-chloride intermediate to the sodium salt of 4-isocyanobenzene is 1:1 to 1:3.

[0028] In the step (2), preferably, the stirring is performed for 15 to 60 minutes.

[0029] In the step (2), the container is not limited. Preferably, the container is equipped with a stirrer and an air guide tube, such as a three-necked round-bottom flask.

[0030] The present invention uses a rhodium (I) atom as the metal center and aromatic isonitriles and 4-isocyanates as ligands to produce an isocyanato rhodium (I) zwitterionic complex. The cationic end is hydrophobic and the anionic end is hydrophilic, exhibiting both hydrophobic and hydrophilic properties. When excited by light in the near-infrared region I with a wavelength of 600 to 800 nm, the isocyanato rhodium (I) zwitterionic complex produces an emission peak at 800 to 1400 nm, i.e., capable of luminescent imaging in the near-infrared region II. Furthermore, the near-infrared luminescence lifetime is greater than 1 microsecond, and the quantum yield is greater than 2%.

[0031] Based on the isocyanate rhodium (I) zwitterion complex of the present invention, the inventors further blended it with hydrophobic PEGylated liposomes. In an aqueous solution, the PEGylated liposomes and the hydrophobic ends of the isocyanate rhodium (I) zwitterion complex are connected together through hydrophobic-hydrophobic interactions, so that the isocyanate rhodium (I) zwitterion complex is encapsulated by the PEGylated liposomes to form isocyanate rhodium (I) zwitterion complex micelles. The hydrophilic ends of the isocyanate rhodium (I) zwitterion complex extend into the aqueous solution, increasing the solubility and dispersibility of the micelles, thereby obtaining a uniformly dispersed micelle aqueous solution. That is, an isocyanate rhodium (I) zwitterion complex micelle comprises the following steps:

[0032] The isocyanate rhodium (I) zwitterion complex is mixed with methanol to obtain a first solution; the PEGylated liposome is mixed with a solvent to obtain a second solution; the first solution and the second solution are evenly mixed to obtain a blended solution, the solvent in the blended solution is removed, and water is added to obtain a blended aqueous solution, wherein the PEGylated liposome encapsulates the isocyanate rhodium (I) zwitterion complex in the aqueous solution through hydrophobic-hydrophobic interaction to form isocyanate rhodium (I) zwitterion complex micelles.

[0033] The PEGylated liposomes include but are not limited to polyethylene glycol-derivatized phosphatidylethanolamine, such as 1,2-distearoylphosphatidylethanolamine-polyethylene glycol 2000 (DSPE-mPEG 2K ), 1,2-distearoylphosphatidylethanolamine-polyethylene glycol 5000 (DSPE-mPEG 5K When the PEGylated liposome is a polyethylene glycol-derivatized phosphatidylethanolamine, the isocyanate rhodium (I) zwitterion complex is encapsulated by the PEGylated liposome to obtain the isocyanate rhodium (I) zwitterion complex micelle. Figure 2 shown.

[0034] The solvent in the second solution is not limited and includes chloroform, tetrahydrofuran, dichloromethane and the like.

[0035] Preferably, the solvent is removed from the blend solution by evaporation.

[0036] Preferably, in the blended solution, the mass ratio of the isocyanide rhodium (I) zwitterion complex to the PEGylated liposomes is 1:5 to 1:15. Further preferably, the PEGylated liposomes completely encapsulate the isocyanide rhodium (I) zwitterion complex to obtain an aqueous solution of isocyanide rhodium (I) zwitterion complex micelles.

[0037] Preferably, when the first solution and the second solution are mixed, the volume ratio of the first solution to the second solution is 1:1 to 1:5.

[0038] The isocyanate rhodium (I) zwitterionic complex micelles have the following beneficial effects:

[0039] (1) The isocyanate rhodium (I) zwitterionic complex micelles have an emission peak in the near-infrared region 1 with a wavelength of 700 to 900 nm, and the emission lifetime is greater than 1 microsecond. The quantum yield is higher than 2%, and can even be higher than 3%.

[0040] (2) The isocyanate rhodium (I) zwitterion complex micelles are formed by encapsulating the isocyanate rhodium (I) zwitterion complex in PEGylated liposomes, and the PEGylated liposomes serve as a diffusion barrier, thereby increasing biocompatibility, having high stability and high biosafety, and being able to perform near-infrared second-zone luminescence imaging in vivo.

[0041] (3) The isocyanate rhodium (I) zwitterion complex micelles can selectively accumulate at the tumor site in vivo and have a long retention time. This effective accumulation and retention effect enables the isocyanate rhodium (I) zwitterion complex micelles to accurately kill tumor tissue without damaging other healthy organs, and has anti-cancer activity.

[0042] Therefore, the isocyanate rhodium (I) zwitterion complex micelles can be applied in the field of biomedicine; for example, they can be used as integrated diagnosis and treatment nanoprobes, called nanodiagnosis and treatment probes, which have near-infrared second-zone luminescence imaging and anti-cancer activity in vivo, and have the advantages of no background autofluorescence interference and high tissue penetration depth; for example, they can be used as anti-cancer drugs.

[0043] When the isocyanate rhodium (I) zwitterion complex micelles are used as nano-diagnostic and therapeutic probes, it is preferred to use near-infrared light with a wavelength greater than 700 nm to excite the nano-diagnostic and therapeutic probes, which can minimize the interference of cell and tissue autofluorescence, thereby obtaining the best imaging contrast and enabling non-destructive imaging in vivo.

[0044] In practical applications, it is preferred that an aqueous solution containing the nano-diagnostic and therapeutic probe is injected into a living body. As a further preference, the concentration of the nano-diagnostic and therapeutic probe is preferably 0.1 to 1 mg / mL. In order to improve the size uniformity of the nano-diagnostic and therapeutic probe, it is preferred that the aqueous solution containing the nano-diagnostic and therapeutic probe is filtered through a filter membrane with a pore size of 100 nm to 500 nm, for example, a filter membrane with a pore size of 100 nm, 200 nm, 220 nm, 250 nm, 300 nm, 400 nm, 450 nm, 500 nm, etc. BRIEF DESCRIPTION OF THE DRAWINGS

[0045] Figure 1 The invention provides a synthetic route for the isocyanorhodium (I) zwitterionic complex.

[0046] Figure 2 The present invention is a schematic diagram of the structural change of isocyanate rhodium (I) zwitterion complex micelles obtained by encapsulating the isocyanate rhodium (I) zwitterion complex with polyethylene glycol derivatized phosphatidylethanolamine.

[0047] Figure 3 The nuclear magnetic hydrogen spectrum of the isocyanate rhodium-chloride intermediate and the isonitrile rhodium (I) zwitterion complex in Example 1 of the present invention is ( 1H NMR) spectrum.

[0048] Figure 4 The nuclear magnetic hydrogen spectrum of the isocyanate rhodium-chloride intermediate and the isonitrile rhodium (I) zwitterion complex in Example 3 of the present invention ( 1 H NMR) spectrum.

[0049] Figure 5 The nuclear magnetic hydrogen spectrum of the isocyanate rhodium-chloride intermediate and the isonitrile rhodium (I) zwitterion complex in Example 4 of the present invention ( 1 H NMR) spectrum.

[0050] Figure 6 The UV-visible absorption spectrum and near-infrared emission spectrum of the isonitrile rhodium (I) zwitterionic complex prepared in Example 1 of the present invention in methanol / water are shown.

[0051] Figure 7 The UV-visible absorption spectrum and near-infrared emission spectrum of the isonitrile rhodium (I) zwitterionic complex prepared in Example 3 of the present invention in methanol / water are shown.

[0052] Figure 8 These are the ultraviolet-visible absorption spectrum and near-infrared emission spectrum of the nanoprobe aqueous solution prepared in Example 1 of the present invention.

[0053] Figure 9 These are the ultraviolet-visible absorption spectrum and near-infrared emission spectrum of the nanoprobe aqueous solution prepared in Example 3 of the present invention.

[0054] Figure 10 The nanoprobes prepared in Examples 1 and 3 of the present invention provide fluorescence imaging, cell cycle and apoptosis images of cancer cells at the cellular level.

[0055] Figure 11 This is a fluorescent imaging image of a nude mouse in vivo of the nanoprobe prepared in Example 3 of the present invention.

[0056] Figure 12 This is an H&E section staining image of the heart, liver, spleen, lung and kidney of mice using the nanoprobes prepared in Examples 1 and 3 of the present invention. DETAILED DESCRIPTION

[0057] The present invention is further described in detail below in conjunction with the embodiments and drawings. It should be pointed out that the embodiments described below are intended to facilitate understanding of the present invention. Some non-essential improvements and adjustments made to the present invention by technicians in this field based on the above-mentioned contents of the present invention still fall within the scope of protection of the present invention.

[0058] Example 1:

[0059] In this embodiment, the isonitrile rhodium (I) zwitter ion complex is a [2,6-dimethyl-1-isocyanatobenzene] 3[4-isocyanatobenzoate ion] rhodium (I) zwitter ion complex, and its preparation method comprises the following steps:

[0060] (1) Under nitrogen protection, 1.5 mmol of 2,6-dimethyl-1-isocyanobenzene, 0.25 mmol of 1,5-cyclooctadiene rhodium chloride dimer, and 5 mL of dichloromethane were added in sequence to a three-necked round-bottom flask equipped with a stirrer and an air guide tube. The mixture was stirred to form a uniform reaction system. The mixture was stirred for 15 minutes, and the solvent was evaporated to obtain [2,6-dimethyl-1-isocyanobenzene] 3-rhodium-chloride intermediate.

[0061] (2) Under nitrogen protection, 1 mmol of [2,6-dimethyl-1-isocyanatobenzene]3-rhodium-chloride intermediate, 1 mmol of sodium 4-isocyanatobenzoate, and 5 mL of methanol were added in sequence to a three-necked round-bottom flask equipped with a stirrer and a gas guide tube. The mixture was stirred to form a uniform reaction system and stirred for 15 minutes. Then, the reaction solution was transferred to a dialysis bag and dialyzed in water for 12 hours. Finally, it was freeze-dried to obtain pure [2,6-dimethyl-1-isocyanatobenzene]3[4-isocyanatobenzoate ion]rhodium (I) zwitterion complex.

[0062] The isonitrile rhodium (I) zwitterion complex is used to prepare isonitrile rhodium (I) zwitterion complex micelles for diagnosis and treatment integrated nanoprobes, which specifically includes the following steps:

[0063] In a round-bottom single-necked bottle, 1 mg of [2,6-dimethyl-1-isocyanatophenyl] 3[4-isocyanatobenzoate ion] rhodium (I) zwitterion complex was dissolved in 1 mL of methanol to obtain a first solution; 10 mg of 1,2-distearoylphosphatidylethanolamine-polyethylene glycol 2000 (DSPE-mPEG 2K ) was dissolved in 3 mL of chloroform to obtain a second solution; the first solution and the second solution were mixed and ultrasonicated to obtain a clear solution; then, the solvent in the reaction flask was removed by rotary evaporation, and 5 mL of ultrapure water was added to the reaction flask of step (1), and ultrasonicated for 5 minutes; finally, the obtained solution was filtered through filter membranes with a pore size of 0.45 μm and 0.22 μm in sequence to obtain a clear aqueous solution containing the nanodiagnostic and therapeutic probe.

[0064] Example 2:

[0065] In this embodiment, the isonitrile rhodium (I) zwitter ion complex is a [1-isocyanatophenyl] 3 [4-isocyanatobenzoate ion] rhodium (I) zwitter ion complex, and its preparation method comprises the following steps:

[0066] (1) Under nitrogen protection, 1.5 mmol of 1-isocyanobenzene, 0.25 mmol of 1,5-cyclooctadiene rhodium chloride dimer, and 6 mL of dichloromethane were added in sequence to a three-necked round-bottom flask equipped with a stirrer and an air guide tube. The mixture was stirred to form a uniform reaction system. The mixture was stirred for 15 min, and the solvent was evaporated to obtain [1-isocyanobenzene] 3-rhodium (I)-chloride intermediate.

[0067] (2) Under nitrogen protection, 1 mmol of [1-isocyanatophenyl]3-rhodium (I)-chloride intermediate, 1 mmol of sodium 4-isocyanatobenzoate, and 5 mL of methanol were added in sequence to a three-necked round-bottom flask equipped with a stirrer and a gas guide tube. The mixture was stirred to form a uniform reaction system and stirred for 20 minutes. Then, the reaction solution was transferred to a dialysis bag and dialyzed in water for 24 hours. Finally, it was freeze-dried to obtain a pure [1-isocyanatophenyl]3-[4-isocyanatobenzoate ion]rhodium (I) zwitterion complex.

[0068] The isonitrile rhodium (I) zwitterion complex is used to prepare isonitrile rhodium (I) zwitterion complex micelles for use in integrated diagnosis and treatment nanoprobes, specifically comprising the following steps:

[0069] In a round-bottom single-mouth bottle, 1 mg of [1-isocyanatophenyl] 3 [4-isocyanatobenzoate ion] rhodium (I) zwitterion complex was dissolved in 1 mL of methanol to obtain a first solution; 10 mg of 1,2-distearoylphosphatidylethanolamine-polyethylene glycol 2000 (DSPE-mPEG 2K ) was dissolved in 3 mL of chloroform to obtain a second solution; the first solution and the second solution were mixed and ultrasonicated to obtain a clear solution; then, the solvent in the reaction flask was removed by rotary evaporation, and 5 mL of ultrapure water was added to the reaction flask, and ultrasonicated for 10 minutes; finally, the obtained solution was filtered through filter membranes with pore sizes of 0.45 μm and 0.22 μm in sequence to obtain a clear aqueous solution containing the nanodiagnostic and therapeutic probe.

[0070] Example 3:

[0071] In this embodiment, the isonitrile rhodium (I) zwitter ion complex is a [2-methyl-1-isocyanonaphthalene] 3 [4-isocyanatobenzoate ion] rhodium (I) zwitter ion complex, and its preparation method comprises the following steps:

[0072] (1) Under nitrogen protection, 3 mmol of 2-methyl-1-isocyanonaphthalene, 0.5 mmol of 1,5-cyclooctadiene rhodium chloride dimer, and 10 mL of methanol were added in sequence to a three-necked round-bottom flask equipped with a stirrer and an air guide tube. The mixture was stirred to form a uniform reaction system. The mixture was stirred for 30 min, and the solvent was removed by rotary evaporation to obtain [2-methyl-1-isocyanonaphthalene] 3-rhodium (I)-chloride intermediate.

[0073] (2) Under nitrogen protection, 3 mmol of [2-methyl-1-isocyanonaphthalene] 3-rhodium (I)-chloride intermediate, 3.3 mmol of sodium 4-isocyanobenzoate, and 5 mL of methanol were added in sequence to a three-necked round-bottom flask equipped with a stirrer and a gas guide tube. The mixture was stirred to form a uniform reaction system and stirred for 20 minutes. The reaction solution was then transferred to a dialysis bag and dialyzed in water for 48 hours. Finally, it was freeze-dried to obtain a pure [2-methyl-1-isocyanonaphthalene] 3-[4-isocyanobenzoate ion] rhodium (I) zwitterionic complex.

[0074] The isonitrile rhodium (I) zwitterion complex is used to prepare isonitrile rhodium (I) zwitterion complex micelles for use in integrated diagnosis and treatment nanoprobes, specifically comprising the following steps:

[0075] In a round-bottom single-mouth bottle, 1 mg of [2-methyl-1-isocyanonaphthalene] 3 [4-isocyanatobenzoate ion] rhodium (I) zwitterion complex was dissolved in 1 mL of methanol to obtain a first solution; 10 mg of 1,2-distearoylphosphatidylethanolamine-polyethylene glycol 2000 (DSPE-mPEG 2K ) was dissolved in 3 mL of chloroform to obtain a second solution; the first solution and the second solution were mixed and ultrasonicated to obtain a clear solution; then, the solvent in the reaction flask was removed by rotary evaporation, and 10 mL of ultrapure water was added to the reaction flask, and ultrasonicated for 10 minutes; finally, the obtained solution was filtered through filter membranes with pore sizes of 0.45 μm and 0.22 μm in sequence to obtain a clear aqueous solution containing the nanodiagnostic and therapeutic probe.

[0076] Example 4:

[0077] In this embodiment, the isonitrile rhodium (I) zwitter ion complex is a [2-isocyanonaphthalene] 3 [4-isocyanatobenzoate ion] rhodium (I) zwitter ion complex, and its preparation method comprises the following steps:

[0078] (1) Under nitrogen protection, 1.5 mmol of 2-isocyanonaphthalene, 0.25 mmol of 1,5-cyclooctadiene rhodium chloride dimer, and 3 mL of methanol were added in sequence to a three-necked round-bottom flask equipped with a stirrer and an air guide tube. The mixture was stirred to form a uniform reaction system. The mixture was stirred for 15 min, and the solvent was removed by rotary evaporation to obtain [2-isocyanonaphthalene]3-rhodium (I)-chloride intermediate.

[0079] (2) Under nitrogen protection, 1 mmol of [2-isocyanonaphthalene]3-rhodium (I)-chloride intermediate, 1 mmol of sodium 4-isocyanobenzoate, and 4 mL of methanol were added in sequence to a three-necked round-bottom flask equipped with a stirrer and a gas guide tube. The mixture was stirred to form a uniform reaction system and stirred for 30 minutes. Then, the reaction solution was transferred to a dialysis bag and dialyzed in water for 24 hours. Finally, it was freeze-dried to obtain a pure [2-isocyanonaphthalene]3-[4-isocyanobenzoate ion]rhodium (I) zwitterion complex.

[0080] The isonitrile rhodium (I) zwitterion complex is used to prepare isonitrile rhodium (I) zwitterion complex micelles for use in integrated diagnosis and treatment nanoprobes, specifically comprising the following steps:

[0081] In a round-bottom single-necked bottle, 1 mg of [2-isocyanonaphthalene] 3 [4-isocyanobenzoate ion] rhodium (I) zwitterion complex was dissolved in 1 mL of methanol to obtain a first solution; 8 mg of 1,2-distearoylphosphatidylethanolamine-polyethylene glycol 5000 (DSPE-mPEG 5K ) was dissolved in 3 mL of chloroform to obtain a second solution; the first solution and the second solution were mixed and ultrasonicated to obtain a clear solution; then, the solvent in the reaction flask was removed by rotary evaporation, and 3 mL of ultrapure water was added to the reaction flask, and ultrasonicated for 20 minutes; finally, the obtained solution was filtered through filter membranes with pore sizes of 0.45 μm and 0.22 μm in sequence to obtain a clear aqueous solution containing the nanoprobe.

[0082] Example 5:

[0083] In this embodiment, the isonitrile rhodium (I) zwitter ion complex is a [1-isocyanonaphthalene] 3 [4-isocyanatobenzoate ion] rhodium (I) zwitter ion complex, and its preparation method comprises the following steps:

[0084] (1) Under nitrogen protection, 1.5 mmol of 2-isocyanonaphthalene, 0.25 mmol of 1,5-cyclooctadiene rhodium chloride dimer, and 5 mL of tetrahydrofuran were added in sequence to a three-necked round-bottom flask equipped with a stirrer and an air guide tube. The mixture was stirred to form a uniform reaction system. The mixture was stirred for 30 min, and the solvent was removed by rotary evaporation to obtain [1-isocyanonaphthalene]3-rhodium (I)-chloride intermediate.

[0085] (2) Under nitrogen protection, 2 mmol of [1-isocyanonaphthalene]3-rhodium (I)-chloride intermediate, 2.8 mmol of sodium 4-isocyanobenzoate, and 6 mL of methanol were added in sequence to a three-necked round-bottom flask equipped with a stirrer and a gas guide tube. The mixture was stirred to form a uniform reaction system and stirred for 20 minutes. Then, the reaction solution was transferred to a dialysis bag and dialyzed in water for 24 hours. Finally, it was freeze-dried to obtain a pure [1-isocyanonaphthalene]3-[4-isocyanobenzoate ion]rhodium (I) zwitterion complex.

[0086] The isonitrile rhodium (I) zwitterion complex is used to prepare isonitrile rhodium (I) zwitterion complex micelles for use in integrated diagnosis and treatment nanoprobes, specifically comprising the following steps:

[0087] In a round-bottom single-mouth bottle, 2 mg of [1-isocyanonaphthalene] 3 [4-isocyanobenzoate ion] rhodium (I) zwitterion complex was dissolved in 1 mL of methanol to obtain a first solution; 15 mg of 1,2-distearoylphosphatidylethanolamine-polyethylene glycol 2000 (DSPE-mPEG 2K ) was dissolved in 3 mL of chloroform to obtain a second solution; the first solution and the second solution were mixed and ultrasonicated to obtain a clear solution; then, the solvent in the reaction flask was removed by rotary evaporation, and 10 mL of ultrapure water was added to the reaction flask, and ultrasonicated for 30 minutes; finally, the obtained solution was filtered through filter membranes with pore sizes of 0.45 μm and 0.22 μm in sequence to obtain a clear aqueous solution containing the nanodiagnostic and therapeutic probe.

[0088] Example 6:

[0089] In this embodiment, the isonitrile rhodium (I) zwitter ion complex is a [2-methyl-1-isocyanonaphthalene] 3[4-isocyanobenzenesulfonate ion] rhodium (I) zwitter ion complex, and its preparation method comprises the following steps:

[0090] (1) Under nitrogen protection, 1.5 mmol of 2-methyl-1-isocyanonaphthalene, 0.25 mmol of 1,5-cyclooctadiene rhodium chloride dimer, and 7 mL of dichloromethane were added in sequence to a three-necked round-bottom flask equipped with a stirrer and an air guide tube. The mixture was stirred to form a uniform reaction system. The mixture was stirred for 25 min, and the solvent was removed by rotary evaporation to obtain [2-methyl-1-isocyanonaphthalene] 3-rhodium (I)-chloride intermediate.

[0091] (2) Under nitrogen protection, 1 mmol of [2-methyl-1-isocyanonaphthalene]3-rhodium (I)-chloride intermediate, 1.2 mmol of sodium 4-isocyanobenzenesulfonate, and 4 mL of dimethyl sulfoxide were added in sequence to a three-necked round-bottom flask equipped with a stirrer and a gas guide tube. The mixture was stirred to form a uniform reaction system and stirred for 30 minutes. Then, the reaction solution was transferred to a dialysis bag and dialyzed in water for 60 hours. Finally, it was freeze-dried to obtain a pure [2-methyl-1-isocyanonaphthalene]3-[4-isocyanobenzenesulfonate ion]rhodium (I) zwitterion complex.

[0092] The isonitrile rhodium (I) zwitterion complex is used to prepare isonitrile rhodium (I) zwitterion complex micelles for diagnosis and treatment integrated nanoprobes, which specifically includes the following steps:

[0093] In a round-bottom single-mouth bottle, 1.5 mg of [2-methyl-1-isocyanonaphthalene] 3 [4-isocyanobenzenesulfonate ion] rhodium (I) zwitterion complex was dissolved in 2 mL of methanol to obtain a first solution; 20 mg of 1,2-distearoylphosphatidylethanolamine-polyethylene glycol 2000 (DSPE-mPEG 2K) was dissolved in 6 mL of chloroform to obtain a second solution; the first solution and the second solution were mixed and ultrasonicated to obtain a clear solution; then, the solvent in the reaction flask was removed by rotary evaporation, and 5 mL of ultrapure water was added to the flask, and ultrasonicated for 20 minutes; finally, the obtained solution was filtered through filter membranes with pore sizes of 0.45 μm and 0.22 μm in sequence to obtain a clear aqueous solution containing the nanodiagnostic and therapeutic probe.

[0094] Example 7:

[0095] In this embodiment, the isonitrile rhodium (I) zwitter ion complex is a [4-isocyanobiphenyl] 3 [4-isocyanobenzoate ion] rhodium (I) zwitter ion complex, and its preparation method comprises the following steps:

[0096] (1) Under nitrogen protection, 1.5 mmol of 4-isocyanobiphenyl, 0.25 mmol of 1,5-cyclooctadiene rhodium chloride dimer, and 5 mL of dichloromethane were added in sequence to a three-necked round-bottom flask equipped with a stirrer and an air guide tube. The mixture was stirred to form a uniform reaction system. The mixture was stirred for 15 minutes, and the solvent was removed by rotary evaporation to obtain [4-isocyanobiphenyl] 3-rhodium-chloride intermediate.

[0097] (2) Under nitrogen protection, 1 mmol of [4-isocyanobiphenyl]3-rhodium-chloro intermediate, 1 mmol of sodium 4-isocyanobenzoate, and 5 mL of methanol were added in sequence to a three-necked round-bottom flask equipped with a stirrer and a gas guide tube. The mixture was stirred to form a uniform reaction system and stirred for 25 minutes. Then, the reaction solution was transferred to a dialysis bag and dialyzed in water for 24 hours. Finally, it was freeze-dried to obtain a pure [4-isocyanobiphenyl]3-[4-isocyanobenzoate ion]rhodium (I) zwitterion complex.

[0098] The isonitrile rhodium (I) zwitterion complex is used to prepare isonitrile rhodium (I) zwitterion complex micelles for use in integrated diagnosis and treatment nanoprobes, specifically comprising the following steps:

[0099] In a round-bottom single-necked bottle, 1 mg of [4-isocyanobiphenyl] 3 [4-isocyanobenzoate ion] rhodium (I) zwitterion complex was dissolved in 1 mL of methanol to obtain a first solution; 10 mg of 1,2-distearoylphosphatidylethanolamine-polyethylene glycol 2000 (DSPE-mPEG 2K ) was dissolved in 3 mL of chloroform to obtain a second solution; the first and second solutions were blended and sonicated to obtain a clear solution. The solvent in the reaction flask was then removed by rotary evaporation, and 8 mL of ultrapure water was added to the reaction flask, followed by sonication for 25 minutes. Finally, the resulting solution was filtered through filter membranes with pore sizes of 0.45 μm and 0.22 μm, respectively, to obtain a clear aqueous solution containing the nanodiagnostic and therapeutic probe.

[0100] Example 8:

[0101] In this embodiment, the isonitrile rhodium (I) zwitter ion complex is a [4-isocyanobiphenyl] 3 [4-isocyanobenzoyloxyethylsulfonate ion] rhodium (I) zwitter ion complex, and its preparation method comprises the following steps:

[0102] (1) Under nitrogen protection, 1.5 mmol of 4-isocyanobiphenyl, 0.25 mmol of 1,5-cyclooctadiene rhodium chloride dimer, and 5 mL of dichloromethane were added in sequence to a three-necked round-bottom flask equipped with a stirrer and an air guide tube. The mixture was stirred to form a uniform reaction system. The mixture was stirred for 15 minutes, and the solvent was removed by rotary evaporation to obtain [4-isocyanobiphenyl] 3-rhodium-chloride intermediate.

[0103] (2) Under nitrogen protection, 1 mmol of [4-isocyanobiphenyl]3-rhodium-chloride intermediate, 1 mmol of sodium 4-isocyanobenzoyloxyethylsulfonate, and 5 mL of methanol were added in sequence to a three-necked round-bottom flask equipped with a stirrer and a gas guide tube. The mixture was stirred to form a uniform reaction system and stirred for 15 minutes. Then, the reaction solution was transferred to a dialysis bag and dialyzed in water for 12 hours. Finally, it was freeze-dried to obtain a pure [4-isocyanobiphenyl]3-[4-isocyanobenzoyloxyethylsulfonate ion]rhodium (I) zwitterion complex.

[0104] The invention discloses a method for preparing isonitrile rhodium (I) zwitterion complex micelles for use in nano-diagnostic and therapeutic probes by using isonitrile rhodium (I) zwitterion complexes, which specifically comprises the following steps:

[0105] In a round-bottom single-mouth bottle, 1 mg of [4-isocyanobiphenyl] 3 [4-isocyanobenzoyloxyethylsulfonate ion] rhodium (I) zwitterion complex was dissolved in 1 mL of methanol to obtain a first solution; 10 mg of 1,2-distearoylphosphatidylethanolamine-polyethylene glycol 2000 (DSPE-mPEG 2K ) was dissolved in 3 mL of chloroform to obtain a second solution; the first solution and the second solution were mixed and ultrasonicated to obtain a clear solution; then, the solvent in the reaction flask was removed by rotary evaporation, and 3 mL of ultrapure water was added to the reaction flask, and ultrasonicated for 30 minutes; finally, the obtained solution was filtered through filter membranes with pore sizes of 0.45 μm and 0.22 μm in sequence to obtain a clear aqueous solution containing the nanodiagnostic and therapeutic probe.

[0106] Example 9:

[0107] In this embodiment, the isonitrile rhodium (I) zwitter ion complex is a [2,6-dimethyl-1-isocyanobenzene] 3[4-isocyanobenzoyloxyethylsulfonate ion] rhodium (I) zwitter ion complex, and its preparation method comprises the following steps:

[0108] (1) Under nitrogen protection, 3 mmol of 2,6-dimethyl-1-isocyanobenzene, 0.5 mmol of 1,5-cyclooctadiene rhodium chloride dimer, and 6 mL of methanol were added in sequence to a three-necked round-bottom flask equipped with a stirrer and an air guide tube. The mixture was stirred to form a uniform reaction system. The mixture was stirred for 30 min, and the solvent was removed by rotary evaporation to obtain [2,6-dimethyl-1-isocyanobenzene] 3-rhodium-chloride intermediate.

[0109] (2) Under nitrogen protection, 3 mmol of [2,6-dimethyl-1-isocyanatobenzene] 3-rhodium-chloride intermediate, 5 mmol of sodium 4-isocyanatobenzoyloxyethylsulfonate, and 5 mL of methanol were added in sequence to a three-necked round-bottom flask equipped with a stirrer and a gas guide tube. The mixture was stirred to form a uniform reaction system and stirred for 15 minutes. Then, the reaction solution was transferred to a dialysis bag and dialyzed in water for 12 hours. Finally, it was freeze-dried to obtain pure [4-isocyanatobiphenyl] 3-[4-isocyanatobenzoyloxyethylsulfonate ion] rhodium (I) zwitterion complex.

[0110] The isonitrile rhodium (I) zwitterion complex is used to prepare isonitrile rhodium (I) zwitterion complex micelles for use in integrated diagnosis and treatment nanoprobes, specifically comprising the following steps:

[0111] In a round-bottom single-mouth bottle, 1 mg of [2,6-dimethyl-1-isocyanatophenyl] 3[4-isocyanatobenzoyloxyethylsulfonate] rhodium (I) zwitterion complex was dissolved in 1 mL of methanol to obtain a first solution; 10 mg of 1,2-distearoylphosphatidylethanolamine-polyethylene glycol 2000 (DSPE-mPEG 2K ) was dissolved in 3 mL of chloroform to obtain a second solution; the first solution and the second solution were mixed and ultrasonicated to obtain a clear solution; then, the solvent in the reaction flask was removed by rotary evaporation, and 10 mL of ultrapure water was added to the flask, and ultrasonicated for 15 minutes; finally, the obtained solution was filtered through filter membranes with pore sizes of 0.45 μm and 0.22 μm in sequence to obtain a clear aqueous solution containing the nanodiagnostic and therapeutic probe.

[0112] Example 10:

[0113] In this embodiment, the isonitrile rhodium (I) zwitter ion complex is a [2-methyl-1-isocyanonaphthalene] 3[4-isocyanatobenzoyloxyethylsulfonate ion] rhodium (I) zwitter ion complex, and its preparation method comprises the following steps:

[0114] (1) Under nitrogen protection, 1.5 mmol of 2-methyl-1-isocyanonaphthalene, 0.25 mmol of 1,5-cyclooctadiene rhodium chloride dimer, and 4 mL of dichloromethane were added in sequence to a three-necked round-bottom flask equipped with a stirrer and an air guide tube. The mixture was stirred to form a uniform reaction system. The mixture was stirred for 30 min, and the solvent was removed by rotary evaporation to obtain [2-methyl-1-isocyanonaphthalene]3 rhodium-chloride intermediate.

[0115] (2) Under nitrogen protection, 1 mmol of [2-methyl-1-isocyanonaphthalene]3-rhodium-chloride intermediate, 3 mmol of sodium 4-isocyanobenzoyloxyethylsulfonate, and 5 mL of methanol were added in sequence to a three-necked round-bottom flask equipped with a stirrer and a gas guide tube. The mixture was stirred to form a uniform reaction system and stirred for 25 minutes. Then, the reaction solution was transferred to a dialysis bag, dialyzed in water for 12 hours, and finally freeze-dried to obtain a pure [2-methyl-1-isocyanonaphthalene]3-[4-isocyanobenzoyloxyethylsulfonate ion]rhodium (I) zwitterion complex.

[0116] The invention discloses a method for preparing isonitrile rhodium (I) zwitterion complex micelles for use in nano-diagnostic and therapeutic probes by using isonitrile rhodium (I) zwitterion complexes, which specifically comprises the following steps:

[0117] In a round-bottom single-necked bottle, 1 mg of [2-methyl-1-isocyanonaphthalene] 3[4-isocyanobenzoyloxyethylsulfonate] rhodium (I) zwitterion complex was dissolved in 1 mL of methanol to obtain a first solution; 10 mg of 1,2-distearoylphosphatidylethanolamine-polyethylene glycol 2000 (DSPE-mPEG) was added. 2K ) was dissolved in 3 mL of chloroform to obtain a second solution; the first and second solutions were blended and sonicated to obtain a clear solution. The solvent in the reaction flask was then removed by rotary evaporation, and 5 mL of ultrapure water was added to the reaction flask, followed by sonication for 25 minutes. Finally, the resulting solution was filtered through filter membranes with pore sizes of 0.45 μm and 0.22 μm, respectively, to obtain a clear aqueous solution containing the nanodiagnostic and therapeutic probe.

[0118] Example 11:

[0119] In this embodiment, the isonitrile rhodium (I) zwitter ion complex is a [2-methyl-1-isocyanonaphthalene] 3[4-isocyanobenzamidoethylsulfonate ion] rhodium (I) zwitter ion complex, and its preparation method comprises the following steps:

[0120] (1) Under nitrogen protection, 1.5 mmol of 2-methyl-1-isocyanonaphthalene, 0.25 mmol of 1,5-cyclooctadiene rhodium chloride dimer, and 5 mL of dichloromethane were added in sequence to a three-necked round-bottom flask equipped with a stirrer and an air guide tube. The mixture was stirred to form a uniform reaction system. The mixture was stirred for 15 min, and the solvent was removed by rotary evaporation to obtain [2-methyl-1-isocyanonaphthalene]3 rhodium-chloride intermediate.

[0121] (2) Under nitrogen protection, 1 mmol of [2-methyl-1-isocyanonaphthalene]3-rhodium-chloride intermediate, 1 mmol of sodium 4-isocyanobenzamidoethylsulfonate, and 5 mL of methanol were added in sequence to a three-necked round-bottom flask equipped with a stirrer and a gas guide tube. The mixture was stirred to form a uniform reaction system and stirred for 10 minutes. Then, the reaction solution was transferred to a dialysis bag and dialyzed in water for 12 hours. Finally, it was freeze-dried to obtain a pure [2-methyl-1-isocyanonaphthalene]3-[4-isocyanobenzamidoethylsulfonate ion]rhodium (I) zwitterion complex.

[0122] The invention discloses a method for preparing isonitrile rhodium (I) zwitterion complex micelles for use in nano-diagnostic and therapeutic probes by using isonitrile rhodium (I) zwitterion complexes, which specifically comprises the following steps:

[0123] In a round-bottom single-mouth bottle, 1 mg of [2-methyl-1-isocyanonaphthalene] 3 [4-isocyanobenzamidoethylsulfonate ion] rhodium (I) zwitterion complex was dissolved in 1 mL of methanol to obtain a first solution; 10 mg of 1,2-distearoylphosphatidylethanolamine-polyethylene glycol 2000 (DSPE-mPEG) was added. 2K ) was dissolved in 1.5 mL of chloroform to obtain a second solution; the first solution and the second solution were mixed and ultrasonicated to obtain a clear solution; then, the solvent in the reaction flask was removed by rotary evaporation, and 8 mL of ultrapure water was added to the reaction flask, and ultrasonicated for 10 minutes; finally, the obtained solution was filtered through filter membranes with pore sizes of 0.45 μm and 0.22 μm in sequence to obtain a clear aqueous solution containing the nanodiagnostic and therapeutic probe.

[0124] Example 12:

[0125] In this embodiment, the isonitrile rhodium (I) zwitter ion complex is a [1-isocyanonaphthalene] 3 [4-isocyanobenzamidoethylsulfonate ion] rhodium (I) zwitter ion complex, and its preparation method comprises the following steps:

[0126] (1) Under nitrogen protection, 1.5 mmol of 1-isocyanonaphthalene, 0.25 mmol of 1,5-cyclooctadiene rhodium chloride dimer, and 5 mL of dichloromethane were added in sequence to a three-necked round-bottom flask equipped with a stirrer and an air guide tube. The mixture was stirred to form a uniform reaction system. The mixture was stirred for 15 min, and the solvent was removed by rotary evaporation to obtain [1-isocyanonaphthalene]3 rhodium-chloride intermediate.

[0127] (2) Under nitrogen protection, 1 mmol of [1-isocyanonaphthalene]3-rhodium-chloro intermediate, 1 mmol of sodium 4-isocyanobenzamidoethylsulfonate, and 5 mL of methanol were added in sequence to a three-necked round-bottom flask equipped with a stirrer and a gas guide tube. The mixture was stirred to form a uniform reaction system and stirred for 15 minutes. Then, the reaction solution was transferred to a dialysis bag and dialyzed in water for 12 hours. Finally, it was freeze-dried to obtain a pure [1-isocyanonaphthalene]3-[4-isocyanobenzamidoethylsulfonate ion]rhodium (I) zwitterion complex.

[0128] The invention discloses a method for preparing isonitrile rhodium (I) zwitterion complex micelles for use in nano-diagnostic and therapeutic probes by using isonitrile rhodium (I) zwitterion complexes, which specifically comprises the following steps:

[0129] In a round-bottom single-necked bottle, 1 mg of [1-isocyanonaphthalene] 3 [4-isocyanobenzamidoethylsulfonate] rhodium (I) zwitterion complex was dissolved in 1 mL of methanol to obtain a first solution; 10 mg of 1,2-distearoylphosphatidylethanolamine-polyethylene glycol 2000 (DSPE-mPEG) was added. 2K ) was dissolved in 3 mL of chloroform to obtain a second solution; the first solution and the second solution were mixed and ultrasonicated to obtain a clear solution; then, the solvent in the reaction flask was removed by rotary evaporation, and 5 mL of ultrapure water was added to the flask, and ultrasonicated for 5 minutes; finally, the obtained solution was filtered through filter membranes with pore sizes of 0.45 μm and 0.22 μm in sequence to obtain a clear aqueous solution containing the nanodiagnostic and therapeutic probe.

[0130] Examples 13-19:

[0131] In Examples 13-19, the preparation method of the isonitrile rhodium (I) zwitterionic complex comprises the following steps:

[0132] (1) Synthesis of isocyanato rhodium-chloride intermediate:

[0133] Under nitrogen protection, in a three-necked round-bottom flask equipped with a stirrer and a gas guide tube, 10-30 mmol of an aromatic isonitrile ligand, 1-5 mmol of 1,5-cyclooctadiene rhodium chloride dimer, and 2-20 ml of a solvent are added in sequence, stirred and mixed to form a uniform reaction system, and stirred for 15-60 minutes to obtain an isonitrile rhodium-chloride intermediate;

[0134] (2) Under nitrogen protection, in a three-necked round-bottom flask equipped with a stirrer and an air guide tube, the isonitrile rhodium-chloride intermediate prepared in step (1), 3-10 mmol 4-isocyanobenzene sodium salt, and 2-20 ml solvent are added in sequence, stirred and mixed to form a uniform reaction system, and stirred for 15-60 minutes to obtain an isonitrile rhodium (I) zwitterionic complex;

[0135] (3) Post-treatment: The reaction solution was transferred into a dialysis bag, dialyzed in water for 12 to 60 h, and finally freeze-dried to obtain a pure solid product.

[0136] The isonitrile rhodium (I) zwitterion complex is used to prepare isonitrile rhodium (I) zwitterion complex micelles for diagnosis and treatment integrated nanoprobes, which specifically includes the following steps:

[0137] In a round-bottom flask, an isocyanorhodium (I) zwitterionic complex is dissolved in methanol to obtain a first solution; PEGylated liposomes are dissolved in a chloroform solution to obtain a second solution; the first solution and the second solution are blended in a certain proportion and ultrasonically obtained to obtain a clear solution; then, the solvent in the reaction flask is removed by rotary evaporation, and a certain amount of ultrapure water is added to the reaction flask to control the concentration of the complex to 0.1 to 1 mg / mL, and ultrasonically obtained for 5 to 30 minutes; finally, the obtained solution is filtered through filter membranes with pore sizes of 0.45 μm and 0.22 μm in sequence to obtain a clear aqueous solution containing the nanodiagnostic and therapeutic probe.

[0138] The raw materials in Examples 13-19 are shown in the table below.

[0139]

[0140]

[0141] In Examples 13-19, the solvent in step (1) is any one of dichloromethane, methanol, tetrahydrofuran and dimethyl sulfoxide.

[0142] In Examples 13-19, the molar ratio of the aromatic isonitrile ligand to the 1,5-cyclooctadiene rhodium chloride dimer in step (1) is 6:1.

[0143] In Examples 13-19, the molar ratio of the isonitrile rhodium-chloride intermediate and 4-isocyanobenzene sodium salt in step (1) is 1:1 to 1:3.

[0144] In Examples 13-19, the volume ratio of the first solution to the second solution is 1:1 to 1:5.

[0145] In Examples 1-19, all raw materials used are commercially available products.

[0146] In Examples 1-19, the amount units of substances used, unless otherwise specified, can be converted into mass (weight) units; the mass (weight) units can all be grams or kilograms.

[0147] In Examples 1-19, the process parameters (temperature, time, etc.) and the amounts of the components in each step are ranges, and any point can be applied.

[0148] In Example 1-19, an isocyanato rhodium-chloride intermediate is first prepared, and then an isonitrile rhodium (I) zwitterionic complex is prepared. The hydrogen atoms in each chemical environment of the obtained compound correspond well to their chemical shifts, and their number is consistent with the peak area. From the nuclear magnetic resonance spectrum analysis of the obtained complex, it can be seen that the target product is obtained according to the method of the present invention. For example, Figure 3-5 The H NMR spectra of the isocyanate rhodium-chloride intermediate and the isonitrile rhodium (I) zwitterionic complex prepared in step (1) of Examples 1, 3 and 4 are respectively ( 1 The H NMR spectrum shows that the hydrogen atoms in various chemical environments of the obtained compound correspond well to their chemical shifts, and their numbers are consistent with the peak areas. From the analysis of the NMR spectrum of the obtained complex, it can be seen that the target product is obtained according to the method of the present invention.

[0149] In Examples 1-19, the prepared isocyanate rhodium (I) zwitterionic complex produces an emission peak at 800-1400 nm under the excitation of near-infrared light with a wavelength of 600-800 nm, that is, it can form images in the near-infrared region 2. For example, Figure 6-7 The UV-visible absorption spectra and near-infrared emission spectra of the isocyanorhodium (I) zwitterionic complexes prepared in Examples 1 and 3 in methanol / water (i.e., a mixed solvent of methanol and water, wherein the volume ratio of methanol to water is 1 / 99) are respectively.

[0150] The isonitrile rhodium (I) zwitterionic complex micelles prepared in Example 1-19 have an emission peak in the near-infrared region 2 at 900 to 1500 nm when excited by light in the near-infrared region 1 with a wavelength of 700 to 900 nm. For example, Figure 8 The UV-visible absorption spectrum and near-infrared emission spectrum of the nanoprobe aqueous solution prepared in Example 1 show that the emission peak of the prepared nanoprobe under the excitation of near-infrared light in the first region with a wavelength of 700-900 nm is located at 1070 nm in the second region of near-infrared. Figure 9 The UV-visible absorption spectrum and near-infrared emission spectrum of the nanoprobe aqueous solution prepared in Example 3 show that the emission peak of the prepared nanoprobe under the excitation of near-infrared light in the first region with a wavelength of 700-900 nm is located at 1129 nm in the second region of near-infrared.

[0151] The nanoprobes prepared in Examples 1-19 were injected into the culture medium of Bel-7404 cells (human liver cancer cells) and incubated for 24 hours. For comparison, some mice were not injected with the nanoprobe aqueous solution, and these mice were marked as the control group. The experiments proved that the nanoprobes prepared in Examples 1-19 have excellent anti-cancer activity. For example, Figure 10Figures 1 and 2 show live cell staining (panel a), cell cycle staining (panel b), and apoptosis staining (panel c) of Bel-7404 cells treated with the nanoprobes prepared in Example 1 and Example 3 after 24 hours of incubation. Panel a shows that only a small number of live cells were present in Example 1, while panels b and c show that the Bel-7404 cells treated with the nanoprobes prepared in Example 1 and Example 3 exhibited a predominantly late-stage apoptotic cell population, demonstrating the excellent anticancer activity of the prepared nanoprobes.

[0152] Bel-7404 cells were implanted into mice, and the aqueous solutions of the nanodiagnostic and therapeutic probes prepared in Examples 1-19 were injected into different groups of mice. For comparison, some mice were not injected with the aqueous solution of the nanodiagnostic and therapeutic probes, and these mice were marked as the control group.

[0153] The control mice and the nanoprobe-treated mice were imaged within 72 hours after injection. The results showed that the nanoprobes prepared in Examples 1-19 had a significant enrichment effect in the tumor and excellent near-infrared phosphorescence imaging, with a retention time of up to 3 days. Therefore, the nanoprobes can monitor the evolution trend of tumors and have great potential in tumor imaging. For example, Figure 11 As shown, the control mouse group showed no phosphorescence signal; while the mouse group treated with the nanoprobes prepared in Example 1 and Example 3 showed obvious phosphorescence signals in the tumor area at the 12th hour, after which the signal gradually increased and showed a strong phosphorescence signal at the 24th hour, and then gradually decreased due to metabolism.

[0154] In order to further study the phosphorescence imaging effect of the nanoprobes prepared in Examples 1-19, the mice treated with the nanoprobes were sacrificed by cervical dislocation at 72 hours, and the tumors and major organ tissues were collected and imaged. Figure 11 As shown in Figure 3, the tumor site showed obvious phosphorescence signals at 72 hours, which is consistent with the above-mentioned phosphorescence imaging results. The phosphorescence in the liver was attributed to the metabolism of the nanoprobe in vivo.

[0155] In addition, the toxicity of the nanoprobes prepared in Examples 1-19 was evaluated by H&E staining of the corresponding tissue sections, which confirmed the safety of the prepared nanoprobes for administration. In addition to being used for tumor phosphorescence imaging, the nanoprobes can also be used as a potential chemotherapeutic drug. For example, Figure 12 As shown in the figure, the tumor cells of the mice treated with the nanoprobes prepared in Example 1 and Example 3 showed obvious apoptotic morphology (nuclear atrophy and fragmentation) 48 hours after administration, while the major organs (heart, liver, spleen, lungs and kidneys) of the mice treated with the nanoprobes showed no obvious pathological changes, which confirmed the safety of the administration of the prepared nanoprobes.

[0156] The embodiments described above provide a detailed description of the technical solutions of the present invention. It should be understood that the above are only specific embodiments of the present invention and are not intended to limit the present invention. Any modifications, supplements or similar substitutions made within the scope of the principles of the present invention should be included in the scope of protection of the present invention.

Claims

1. An isocyanate rhodium (I) zwitterionic complex, characterized by: Its chemical structural formula is: ， Wherein, Ar is one or more of the following: ； R is one of the following: 。 2. The isocyanate rhodium (I) zwitterionic complex according to claim 1, wherein: When excited by light in the near-infrared region with a wavelength of 600 to 800 nm, the emission peak is located at 800 to 1400 nm.

3. The isocyanate rhodium (I) zwitterionic complex according to claim 1, wherein: Their near-infrared luminescence lifetimes are greater than 1 microsecond, and their quantum yields are higher than 2%.

4. A method for synthesizing the isocyanate rhodium (I) zwitterionic complex according to any one of claims 1 to 3, characterized in that: The steps include: (1) Under nitrogen protection, an aromatic isonitrile ligand, 1,5-cyclooctadiene rhodium chloride dimer and a solvent are added to a container and mixed uniformly to obtain an isonitrile rhodium-chloride intermediate; the aromatic isonitrile ligand is one or more of 1-isocyanobenzene, 2,6-dimethyl-1-isocyanobenzene, 2-isocyanonaphthalene, 1-isocyanonaphthalene, 2-methyl-1-isocyanonaphthalene and 4-isocyanobiphenyl; (2) Under nitrogen protection, the isonitrile rhodium-chloride intermediate prepared in step (1), 4-isocyanobenzene sodium salt and a solvent are added to a container and mixed uniformly to obtain an isonitrile rhodium (I) zwitterionic complex; the 4-isocyanobenzene sodium salt is one of sodium 4-isocyanobenzoate, sodium 4-isocyanobenzenesulfonate, sodium 4-isocyanobenzoyloxyethylsulfonate and sodium 4-isocyanobenzeneamidoethylsulfonate.

5. The synthesis method according to claim 4, wherein: The solution after the reaction in step (2) was transferred into a dialysis bag, dialyzed in water, and then freeze-dried to obtain a pure solid product.

6. The synthesis method according to claim 4, wherein: In the step (1), the solvent is one or more of dichloromethane, methanol, tetrahydrofuran, and dimethyl sulfoxide.

7. The synthesis method according to claim 4, wherein: In the step (2), the solvent is one or more of dichloromethane, methanol, tetrahydrofuran, and dimethyl sulfoxide.

8. The synthesis method according to claim 4, wherein: In the step (1), the molar ratio of the aromatic isonitrile ligand to the 1,5-cyclooctadiene rhodium chloride dimer is 6:

1.

9. The synthesis method according to claim 4, wherein: In the step (2), the molar ratio of the isonitrile rhodium-chloride intermediate to the sodium salt of 4-isocyanobenzene is 1:1 to 1:

3.

10. An isocyanate rhodium (I) zwitterion complex micelle, characterized in that: In a container, the isocyanate rhodium (I) zwitterion complex according to any one of claims 1 to 3 is mixed with methanol to obtain a first solution; PEGylated liposomes are mixed with a solvent to obtain a second solution; the first solution and the second solution are evenly mixed to obtain a blended solution, the solvent in the blended solution is removed and water is added to obtain a blended aqueous solution, and the PEGylated liposomes encapsulate the isocyanate rhodium (I) zwitterion complex in the aqueous solution through hydrophobic-hydrophobic interaction to form isocyanate rhodium (I) zwitterion complex micelles.

11. The isocyanate rhodium (I) zwitterionic complex micelle according to claim 10, characterized in that: The solvent in the second solution is one or more of chloroform, tetrahydrofuran and dichloromethane.

12. The isocyanate rhodium (I) zwitterionic complex micelle according to claim 10, characterized in that: In the blended solution, the mass ratio of the isocyanate rhodium (I) zwitterionic complex to the PEGylated liposome is 1:5 to 1:

15.

13. The isocyanate rhodium (I) zwitterionic complex micelle according to claim 10, characterized in that: The PEGylated liposomes completely encapsulated the isocyanate rhodium (I) zwitterion complex to obtain an aqueous solution of isocyanate rhodium (I) zwitterion complex micelles.

14. The isocyanate rhodium (I) zwitterionic complex micelle according to claim 10, characterized in that: When the first solution and the second solution are mixed, the volume ratio of the first solution to the second solution is 1:1 to 1:

5.

15. The isocyanate rhodium (I) zwitterionic complex micelle according to claim 10, characterized in that: The PEGylated liposomes are polyethylene glycol-derivatized phosphatidylethanolamine.

16. The isocyanate rhodium (I) zwitterionic complex micelle according to claim 15, characterized in that: The polyethylene glycol-derivatized phosphatidylethanolamine is one or both of 1,2-distearoylphosphatidylethanolamine-polyethylene glycol 2000 and 1,2-distearoylphosphatidylethanolamine-polyethylene glycol 5000.

17. The isocyanate rhodium (I) zwitterionic complex micelle according to claim 10, characterized in that: The emission peak generated under the excitation of near-infrared light in the first region with a wavelength of 700 to 900 nm is located in the near-infrared second region of 900 to 1500 nm.

18. The isocyanate rhodium (I) zwitterionic complex micelle according to claim 10, characterized in that: Their near-infrared luminescence lifetimes are greater than 1 microsecond, and their quantum yields are higher than 3%.

19. The isocyanate rhodium (I) zwitterionic complex micelle according to claim 10, characterized in that: It has near-infrared second-zone luminescence imaging and anti-cancer activity.

20. A nano-diagnostic probe, characterized by: The isocyanate rhodium (I) zwitterionic complex micelle according to any one of claims 10 to 19 is used.

21. The nano-diagnostic probe according to claim 20, wherein: The nano-diagnostic and therapeutic probe is excited by near-infrared light with a wavelength greater than 700 nm.

22. The nano-diagnostic probe according to claim 20, wherein: The nano-diagnostic and therapeutic probe is dispersed in water, and the concentration of the nano-diagnostic and therapeutic probe is 0.1-1 mg / mL.

23. An anticancer drug, characterized by: The invention comprises the isocyanate rhodium (I) zwitterion complex micelle according to any one of claims 10 to 19.

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